The depletion of bone or skeletal calcium is a characteristic of osteoporosis where the bone is histologically normal. The loss may be of the cortical and/or trabecular bone mass, the former constituting about 80% of skeletal bone and forms the dense outer layer of bone; while trabecular bone constitutes the interior of bone and forms a reticulated matrix which provides such bone with a greater surface area per unit volume than cortical bone, and consequently, a much higher rate of bone resorption and formation (turnover); loss about 8.times.faster than is cortical bone. Before bone loss begins, there is a dynamic balance or coupling between formation and resorption of bone with new bone being continuously formed and old bone resorbed. After some 30 or 40 years uncoupling begins. During coupling there is a balance between the action of the osteoclasts and the osteoblasts. A negative balance results in osteoporosis. It is not clearly established whether this uncoupling is due to a deficiency of osteoblasts (formation) or to an increase in osteoclast (resorption) activity; especially since it is not universally found that osteoblast dysfunction results in osteoporosis. Clinically, the manifestation of the disease are low-energy fractures. Of the therapies used to reduce the risk of fractures by reducing the loss of bone are (1) increasing dietary calcium, (2) use of fluorides, (3) combination of calcium and fluorides, (4) estrogen, (5) thiazides, (6) calcitonin, (7) mithramycin, (8) certain phosphonates, and (9) a variety of inhibitors for thyroid hormone (RTH)-stimulated bone resorption such as thiophene 2-carboxylic, indole-2-carboxylic, thionaphthene-2-carboxylic acid among others. While there is no clinical hypercalcemic condition present in osteoporosis among the new approaches to the treatment of osteoporosis has been the use of materials with hypoccalcemic activity, i.e., lowering of the serum calcium, which is believed to be related to an indicative of a decrease in the rate of bone resorption. Calcitonin, mithramycin (an antibiotic) and certain phosphonates are representative hypocalcemic agents, but adverse effects and lack of effectiveness in bone-loss prevention associated with the use of such agents, make continued research necessary.
In recent U.S. Pat. Nos. 4,101,668 (issued Jul. 18, 1978), 4,125,621 (issued Nov. 14, 1978) and 4,185,108 (issued Jan. 22, 1980), all three having as inventors C. M. Samour and J. A. Vida, there are disclosed a wide variety of benzo-heterocyclic compounds for use as antiosteoporotic agents. Among the specific compounds described are thionaphthene-2-carboxylic acid, thionaphthene-3-carboxylic acid, thionaphthene-4-carboxylic acid, dibenzothiophene-4-carboxylic acid, thioxanthene-9-one-4-carboxylic acid and indole-2-carboxylic acid.
The compounds are compared to thyrocalcitonin (TCT), the latter, a bone-remodeling hormone which is capable of reducing bone resorption rates. In the patented disclosures, the effectiveness of any bone resorption modifying agent is determined by measuring the effect on the production of cyclic adenosine-3'5'-monophosphate (c-AMP) using the methods of Rodan et al, J. B. C. Vol 429, page 306, 1974; Rodan et al, Science, Vol. 189, page 467, 1975. In the comparison, the activity shown by the free acid compounds covered by the disclosure of the aforementioned patents ranges from slightly more than half as effective to twice as effective as TCT in stimulating the production of c-AMP.
In contrast to the histologically normal bone resorption resulting from osteoporosis, we also have the more serious osteomalacia or osteitis fibrosa cystica which are illustrative of abnormalities characterized by hypercalcemia.
The most common causes of hypercalcemia are primary hyperparathyroidism and malignant diseases. Total normal plasma calcium concentration ranges from 8.5 to 10.7 mg/dl with about half circulating as free calcium ions. It is the ionized calcium concentration that regulates neuromuscular contractability as well as a variety of other cellular activites. Hypercalcemia occurs when the calcium entry into the blood compartment is greater than the rate of its removal.
In general, patients with mild hypercalcemia (less than 12 mg/dl) do not have symptoms of hypercalcemia and do not experience significant clinical improvement when their calcium level is normalized. Thus, immediate therapeutic intervention is not usually necessary. The decision to treat a patient with moderate hypercalcemia (12 to 14 mg/dl) depends somewhat upon whether the patient is experiencing significant symptoms and also upon the etiology. Usually, however, a series of general measures is instituted at this point (Table I). Most of the therapeutic maneuvers lower serum calcium by increasing urinary calcium excretion.
Hydration is central to the management of hypercalcemia because the pathophysiologic events induced by hypercalcemia (defective renal concentrating mechanism, polyuria, anorexia, nausea, vomiting) invariably cause dehydration and further elevate the serum calcium. A significant decline in the serum calcium level may result simply from restoration of the intravascular volume and glomerular filtration. Rehydration with intravenous saline also has the advantage of improving renal calcium clearance since the degree of calcium excretion is directly linked to the degree of sodium excretion. It is important to use caution in the administration of normal saline, particularly in the elderly or those with cardiovascular or renal disease. The use of a loop diuretic such as furosemide to facilitate sodium and calcium losses may be beneficial in such patients.
TABLE I ______________________________________ Management of Hypercalcemia General Specific ______________________________________ Hydration Mithramycin Saline diuresis Bisphosphonates Diuresis with loop diuretics Calcitonin Dialysis Phosphate Mobilization WR 2721 (not generally available) Gallium nitrate Corticosteroids Therapy of underlying etiology ______________________________________
Another general measure that is usually reserved for the severely hypercalcemic individual is dialysis. Peritoneal or hemodialysis with a low calcium dialysate will lower serum calcium in those patients who are refractory to other measures or who have renal failure.
Patients with severe hypercalcemia (greater than 14 mg/ml) or those who are symptomatic require urgent therapy because they are at significant risk for developing neurologic dysfunction as well as irreversible cardiovascular and renal damage. Excessive calcium mobilization from the skeleton, one of the common pathophysiologic process leading to hypercalcemia, is generally readily controlled by agents that inhibit osteoclast-mediated bone resorption. Mithramycin, a specific inhibitor of osteoclast function, will generally reduce serum calcium regardless of the underlying etiology. A dose of 15-25 ug/kg is administered intravenously over 2 to 4 hours. The infusion is repeated as necessary at 2-4 day intervals. Although side effects of Mithramycin (kidney, liver and bone marrow toxicity) make it of limited usefulness in the setting of chronic hypercalcemia, it is the drug of choice for most life-threatening hypercalcemias.
The bisphosphonates also directly inhibit osteoclast-mediated bone resorption. In the United States, the only available bisphosphonate is ethane hydroxy 1,1-diphosphonic acid (EHDP). EHDP, administered as a daily 2 hour infusion for 3-5 days at a dose of 7.5 mg/kg effectively lowers serum calcium in most settings of increased bone resorption. Other more potent bisphosphonates may be available in the near future.
While calcitonin should theoretically be an ideal agent because it both impairs osteoclast function and increases urinary calcium excretion, it is not as effective as either mithramycin or bisphosphonates. Intravenous phosphate therapy markedly lowers serum calcium, but the associated widespread ectopic soft tissue deposition of calcium-phosphate complexes makes it an unacceptable choice. Oral phosphate therapy may be used to lower serum calcium in patients with low or normal serum phosphorus concentrations but it is not useful in situations of severe hypercalcemia. Doses of less than 3 g per day usually are well tolerated in terms of side effects such as diarrhea.
In patients in whom increased intestinal calcium absorption may constitute a major contributing factor in the pathogenesis of hypercalcemia, glucocorticoids may be effective therapy. Conditions associated with excessive production of vitamin D metabolites (sarcoidosis, vitamin D toxicity, certain lymphomas) fall into this category. Corticosteroids inhibit vitamin D-mediated intestinal calcium transport. In these patients, restriction of both dietary calcium intake and sunlight exposure may also help to control serum calcium.
Specific clinical syndromes characterized by hypercalcemia include "Humoral Hypercalcemia of Malignancy" or "HHM". Many tumors give rise to this syndrome, such as squamous carcinomas (lung, esophagus, cervix, vulva, skin, head and neck), renal bladder and ovarian carcinomas. Breast carcinomas may cause either typical HHM or may lead to hypercalcemia through skeletal metastatic involvement. It has been stated that patients with HHM account for up to 80 percent of patients with malignancy-associated hypercalcemia.
Almost all patients with myeloma have extensive bone destruction. This may occur either as discrete local lesions or diffuse involvement throughout the axial skeleton. This increased bone resorption is responsible for many disabling features including fracture, intractable bone pain and, in some patients hypercalcemia. The bone destruction Which occurs in myeloma is due to an increase in the activity of osteoclasts. It has been found that cytokine lymphotoxin is the major bone resorbing factor produced by cultured human myeloma cells. Clearly there is a great need for safe and effective agents to act in an anti-hypercalcemic capacity.